Real-World Safety of Trastuzumab Deruxtecan in Patients with HER2-Positive and HER2-Low Metastatic Breast Cancer in Saudi Arabia: A Retrospective Cohort Study.

Introduction: Trastuzumab deruxtecan (T-DXd) has become an important treatment option for patients with HER2-positive and HER2-low solid tumors, yet real-world evidence on its safety remains limited, particularly in Middle Eastern populations. This study evaluates the safety profile of T-DXd in routine clinical practice at a major tertiary center in Makkah, Saudi Arabia. Methods: A retrospective cohort study was conducted at King Abdullah Medical City and included adults with HER2-positive or HER2-low metastatic breast cancer who received at least one dose of T-DXd between 2022 and 2024. Electronic medical records were reviewed for demographic data, prior treatments, and adverse events. Toxicities were graded according to CTCAE v5.0. The primary outcome was the incidence and severity of T-DXd-related adverse events. Secondary outcomes included treatment discontinuation rates and adherence to recommended interstitial lung disease (ILD) monitoring protocols. Results: Thirty-one patients were included (93.5% female; median age 50-59 years). Hematologic toxicities were most common, occurring in 87.1% of patients. Respiratory events including ILD and pneumonitis were documented in 28% of patients. Among patients who underwent imaging according to recommended intervals, respiratory events were identified more frequently (36%) than in those with less consistent monitoring (11%), likely reflecting increased detection of subclinical events rather than a true difference in incidence. Treatment discontinuation occurred in 25.8% of patients, primarily due to adverse events or progression. Conclusion: T-DXd was generally tolerable in this small Saudi cohort, with hematologic and respiratory toxicities being the most frequent. The relatively higher frequency of respiratory events and the observed differences by monitoring adherence should be interpreted cautiously given the descriptive design. Larger multicenter studies are needed to better define safety patterns and optimal monitoring strategies.